Targeted protein degradation has become an exciting new drug modality. Tens of small molecule degraders, including proteolysis-targeting chimeras (PROTACs), have entered clinical trials to treat many different diseases.

PROTACs are heterobifunctional molecules that recruit a target protein to an enzyme called E3 ubiquitin ligase, which then marks the target protein for degradation by the cell’s own waste disposal machinery, namely the proteasome. Where a target protein is located within the cell could therefore have an influence on how well the target protein is degraded by PROTACs but this was unknown.

Research in the Sapkota group led by PhD students Lorraine Glennie and Luke Simpson discovered that the protein’s location within distinct subcellular compartments as well as the nature of the E3 ubiquitin ligase recruited by the PROTAC both affected the ability of the PROTAC to cause target protein degradation. They localised target proteins to the nucleus, cytoplasm, outer mitochondrial membrane, endoplasmic reticulum, golgi, peroxisome and lysosome and tested the ability of PROTACs recruiting two different E3 ubiquitin ligases (either cereblon or von Hippel-Lindau protein) to degrade these differentially localised proteins. Observed variations in the levels of target protein degradation caused by the same PROTAC on the same target protein localised to different subcellular compartments suggests that a particular subcellular context is an important consideration for PROTAC-mediated degradation.

The findings are described in the current issue of Cell Chemical Biology - see here

Abigail Brewer and Jin-Feng Zhao from the Sapkota lab and Jennifer Crooks from the MRC PPU Reagents and Services also contributed to the study. Natalia Shpiro from the MRC PPU synthesized some of the PROTACs used in this study.